It has recently been discovered that certain macrocyclic compounds are potent and specific inhibitors of hepatitis C virus (HCV) protease. In particular, compounds of the following formula I have been found to be an especially potent class of inhibitors against the NS3 serine protease of HCV:
wherein:    —designates an optional bond forming a double bond between positions 13 and 14;    R1 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R5)2, wherein each R5 is independently H, C1-6 alkyl or C3-6 cycloalkyl;    L1, L2 are each independently H, halogen, C1-4alkyl, —O—C1-4alkyl, or —S—C1-4alkyl (the sulfur being in any oxidized state);    R2 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C6 or 10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four ring heteroatoms selected from nitrogen, oxygen and sulfur;    said cycloalkyl, aryl or Het being optionally substituted with R6,    wherein R6 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R7)2, NH—C(O)—R7; or NH—C(O)—NH—R7, wherein each R7 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;or R6 is NH—C(O)—OR8 wherein R8 is C1-6 alkyl or C3-6 cycloalkyl;    R3 is R9O— or R9NH—, wherein R9 is C1-6alkyl or C3-6cycloalkyl;    R4 is H or from one to three substituents on any available carbon atom at positions 8, 9, 10, 11, 12, 13 or 14, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio or C1-6 thioalkyl;
See Tsantrizos et al., U.S. application Ser. No. 09/760,946, filed on Jan. 16, 2001, now U.S. Pat. No. 6,608,027 B1 (Boehringer Ingelheim (Canada), Ltd.), which is herein incorporated by reference in its entirety and is hereinafter referred to as “Tsantrizos et al”. See also the corresponding WO 00/59929. In addition, see Llinas-Brunet, U.S. Provisional Application No. 60/504,839, filed on Sep. 22, 2003, which is herein incorporated by reference in its entirety and is hereinafter referred to as “Llinas-Brunet”.
A structural feature of the compounds of formula I is the presence of the C-terminal carboxylic acid functionality, which was shown to be responsible not only for the potency and reversibility observed for this inhibitor series, but also for the excellent specificity for HCV protease compared to other serine/cysteine proteases. An HCV serine protease inhibitor such as the compounds of formula I would be expected to be an antiviral agent acting via a novel mechanism, i.e. blockage of a virus-encoded essential function for HCV replication. A drug acting through this mechanism should suppress viral replication of all HCV genotypes and therefore provide tangible benefits to patients with chronic hepatitis C.
A common problem among protease inhibitors is that these compounds are lipophilic and have low aqueous solubility. Because of the poor aqueous solubility, conventional solid and liquid pharmaceutical preparations containing these inhibitors may not be absorbed by the patient in a satisfactory manner. Of the various factors that can affect the bioavailability of a drug when administered orally, (which include aqueous solubility, drug absorption through the gastrointestinal tract, dosage strength and first pass effect), aqueous solubility is often found to be among the most important factors. Poorly water soluble compounds often exhibit either erratic or incomplete absorption in the digestive tract, and thus produce a less than desirable response.
The compounds of formula I are zwitterionic and are capable of forming salts with strong acids and bases. Attempts to identify salts of such compounds in solid forms, which would substantially improve aqueous solubility, have not been successful. Various salts of these compounds have been found to be very hygroscopic, reducing the stability of the compounds. In addition, formulations of salts of these compounds generally are prone to precipitation of the parent free-acid in the gastrointestinal tract. Representative compounds of formula I have shown poor bioavailability when administered to animals as an aqueous suspension, suggesting that conventional formulations containing these inhibitors may not be absorbed in a satisfactory manner. Thus, there is a need in the art for pharmaceutical compositions of the formula I compounds having improved bioavailability.
Methods of formulating certain lipophilic macrocyclic compounds into pharmaceutical formulations have been previously reported. For example, Cavanak, U.S. Pat. No. 4,388,307, discloses the preparation of emulsified formulations of commercially available cyclosporins, and Hauer et.al, U.S. Pat. No. 5,342,625, and Meizner et al. WO 93/20833 disclose the preparation of cyclosporin microemulsions and microemulsion pre-concentrates. Komiya et. al, U.S. Pat. No. 5,504,068, further discloses the preparation of an enhanced topical formulations of cyclosporin.
Examples of “self-emulsifying” formulations of lipophilic compounds include Lipari et al, WO 96/36316, which discloses a self-emulsifying pre-concentrate comprising a lipophilic compound, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) and a lipophilic phase. Gao et al., U.S. Pat. No. 6,121,313 discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising the pyranone compound, a mixture of mono- and di-glycerides, one or more solvents and one or more surfactants; and Gao et al, U.S. Pat. No. 6,231,887 B1 discloses a self-emulsifying formulation of a pyranone protease inhibitor comprising the pyranone compound, an amine, one or more solvents and one or more surfactants.
Yu et. al U.S. Pat. Nos. 5,360,615 and 5,071,643 disclose the preparation of a solvent system for enhancing the solubility of acidic, basic or amphoteric compounds by partial ionization comprising a mixture of polyethylene glycol, hydroxide or hydrogen ion, and water. Morton et al U.S. Pat. No. 5,376,688 discloses solutions of acidic, basic or amphoteric pharmaceutical agents comprising the pharmaceutical agent, an ionic species and a solvent system. Bhagwat et. al U.S. Pat. No. 6,056,977 teaches the use of polysaccharide based matrix for sustained release of a sulfonylurea.
A self-emulsifying drug delivery system (SEDDS) having improved bioavailability has recently been developed for the compounds of formula (I), as described in U.S. application Ser. No. 10/357,919 (S. Chen et al.), filed Feb. 4, 2003, now U.S. Pat. No. 6,828,301, and in PCT/US03/03380 (Boehringer Ingelheim Pharmaceuticals, Inc.), filed Feb.5, 2003, published as WO 03/066103 A1. This formulation comprises a compound of formula (I), about 0.1 to 10% by weight of a pharmaceutically acceptable amine or a mixture of pharmaceutically acceptable amines, one or more pharmaceutically acceptable oils, optionally one or more pharmaceutically acceptable hydrophilic solvents, optionally one or more pharmaceutically acceptable polymers, and optionally one or more pharmaceutically acceptable surfactants. However, it has been found that this formulation may not be fully optimized with respect to its chemical stability and therefore may require storage under refrigerated conditions.